The National Institutes of Health considers the development of therapeutics against potential bioterrorism agents a national research priority. There is a particular need for immunotherapeutics against Ebola virus (a Category A agent). Because of Ebola's lethality and reports that it has been weaponized, public health officials and defense agencies have mounted a concerted effort to encourage development of countermeasures for protecting civilian and military populations. There are currently no drugs available for preventing or treating Ebola virus infection. Passive immunization with antibodies has been shown to be effective against a wide variety of viruses. Because of their excellent safety profile and efficacy, monoclonal antibodies (mAbs) are a rapidly growing class of therapeutic drugs. Mapp has been developing MB-2003, a mAb based anti-Ebola product. The current configuration of MB-2003 consists of 3 mAbs that individually and in combination have been shown to provide significant prophylactic and therapeutic protection in mice. As a result of completion of the Phase 1 activities, the MB-2003 cocktail has also been shown to provide 100% protection in macaques against a highly lethal challenge. This is the first time antibodies have been shown to protect primates against Ebola - previous experiments with polyclonal or monoclonal antibodies have failed to provide any protection. Because of the rapid onset and high lethality of Ebola virus, we anticipate the MB-2003 product will be administered intravenously as a pre-exposure and/or post-exposure prophylactic. The Specific Aims of this proposal are: Specific Aim 1. Determine the final MB-2003 product configuration. Tests in the macaque model will determine whether the final MB-2003 configuration will be one, two, or three mAbs. Dose ranging studies will be performed to identify the protective dose, and time course experiments will determine the therapeutic window for MB-2003. Specific Aim 2. Finalize the MB-2003 liquid formulation. An optimal liquid formulation for the mAb(s) selected in Aim 1 will be identified in collaboration with Formatech (Andover, MA). Specific Aim 3. Complete IND-enabling testing and submit an IND. MB-2003 will be manufactured and formulated under current Good Manufacturing Practices (cGMP). All IND- enabling pharmacology, toxicology, and Chemistry, Manufacturing and Controls (CMC) studies will be performed, with a final goal of filing an IND to support a Phase 1 human safety trial. PUBLIC HEALTH RELEVANCE: The efforts in this proposal will help in the development of a drug for preventing and/or treating Ebola virus infection, a potential biowarfare agent, for which no treatment currently exists.